Durvalumab and Endocrine Therapy in ER+/Her2- Breast Cancer After CD8+ Infiltration Effective Immune-Attractant Exposure

NCT02997995 | Completed Phase 2 DMC

• 4 other identifiers: UC-0140/1606UCBG-105BIG 16-012016-000764-42
• Study Type: interventional
• Target: 61
• Locations: 3 countries
• Sites: 29

Brief Summary

This is an open-label, multicentric, international, phase II trial testing aromatase inhibitors in combination with durvalumab in patients with CD8+ T cell infiltration (\>10% CD8+ T cells in the tumor). The trial includes two sequences: The first part of the treatment will consist in 4-6 weeks treatment with immune-attractants; in the second part, CD8+ patients will receive 6 months of durvalumab combined with exemestane.

Conditions

Breast Cancer; Estrogen Receptor Positive Tumor; Menopause; Hormone Antagonist

Keywords

T2-T4 Breast cancer; Estrogen Receptor Positive Tumor; PD-1; Neoadjuvant; Immune-attractants; lymphocytes activation

Outcome Measures

Primary Outcomes (1)

• pathological Complete Response

  Response at surgery

  at time of surgery

Secondary Outcomes (6)

• Number of CD8+ T cell

  at biopsy (3 weeks)

• Clinical response

  after 6 months of Durvalumab

• Assessment of Ki67

  at surgery

• Toxicities

  1 year and 8 months

• Predictive value of Mutational load for efficacy of Durvalumab

  on baseline biopsy and blood samples

Study Arms (1)

Immune-attractant/lymphocyte activation

EXPERIMENTAL

After the screening phase, the patient will receive immune-attractant combined with exemestane for six weeks. After three weeks (+/- 3 days), a tumor biopsy will be done. Patients who present \>10% CD8+ cells in the tumor after 3 weeks and remain eligible will be included in the second part of the trial i.e. lymphocyte activation. In this second part, patients will receive durvalumab 1500 mg Q4W (equivalent to 20 mg/kg Q4W) IV, combined with exemestane (25 mg daily), for six months. The pathological response will be checked by surgery.

Drug: Immune-attractant; Drug: Durvalumab; Procedure: Biopsy

Interventions

Immune-attractant DRUG

The first cohort patients will receive tremelimumab (3 mg/kg, single infusion) as immune-attractants combined with exemestane (25 mg daily).

Also known as: Tremelimumab

Immune-attractant/lymphocyte activation

Durvalumab DRUG

Durvalumab (lymphocyte activation) will be administrated at a dose of 1500 mg Q4W (equivalent to 20 mg/kg Q4W) IV, combined with exemestane (25 mg daily), for six months

Also known as: MEDI4736

Immune-attractant/lymphocyte activation

Biopsy PROCEDURE

After three weeks (+/- 3 days) of immune-attractants, a tumor biopsy will be done. Patients who present \>10% CD8+ cells in the tumor after 3 weeks will receive the Durvalumab

Immune-attractant/lymphocyte activation

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥18 years post-menopausal according to one of the following criteria:
• Age \>60 years
• Or Bilateral ovariectomy
• Or Age ≤60, with an uterus and presenting an amenorrhea of more than 12 months and FSH and estradiol in the postmenopausal range
• Or Age ≤60, without an uterus and FSH and estradiol in the postmenopausal range
• Histologically proven invasive breast cancer eligible to neoadjuvant endocrine therapy according to multidisciplinary tumor board.
• Note: Multicentric/multifocal tumors are allowed if all share the same characteristics
• cT2-T4, any N; cT2 are eligible only if the clinical tumor size is \>3 cm
• Non metastatic, M0 (according to clinical staging)
• Luminal A patients ER-positive by immunohistochemistry (IHC) according to the following criteria (local assessment): Grade I or II AND ER-positive (≥60%) AND Ki67 \<20%
• Her2-negative by IHC (score 0 or 1+) and/or fluorescent in situ hybridization (FISH)/chromogenic in situ hybridization (CISH) negative according to local assessment
• Available tumor samples from baseline biopsy
• World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at enrolment
• Adequate organ and marrow function as defined below:
• Hemoglobin ≥9.0 g/dL

You may not qualify if:

• Inflammatory breast cancer
• No prior exposure to immune-mediated therapy including, but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-programmed cell death ligand 2 (anti-PD-L2) antibodies, excluding therapeutic anticancer vaccines
• Any concurrent chemotherapy, investigational product (IP), biologic therapy for cancer treatment
• Previous Radiotherapy treatment to more than 30% of the bone marrow;
• Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose
• History of allogenic organ transplantation
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[eg, colitis or Crohn's disease\], diverticulitis with the exception of diverticulosis, celiac disease or other serious gastrointestinal chronic conditions associated with diarrhea), systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome (granulomatosis with polyangiitis), Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc within the past 3 years prior to the start of treatment. The following are exceptions to this criterion:
• Patients with vitiligo or alopecia
• Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement or psoriasis not requiring systemic treatment
• Any condition that, in the opinion of the Investigator, would interfere with the evaluation of investigational product or interpretation of patient safety or study results, including ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring adverse events from investigational products, or compromise the ability of the patient to give written informed consent
• Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms
• History of active primary immunodeficiency
• Known history of active tuberculosis
• Active infection including hepatitis B, hepatitis C, or human immunodeficiency virus (HIV)
• Current or prior use of immunosuppressive medication within 14 days before the first dose. The following are exceptions to this criterion:

Sponsors & Collaborators

• UNICANCER: lead
• Breast International Group: collaborator

Study Sites (29)

Centre Hospitalier cote Basque

Bayonne, 64109, France

Location

Institut Bergonié

Bordeaux, 33000, France

Location

Centre François Baclesse

Caen, France

Location

Centre Hospitalier de Cahors

Cahors, 46000, France

Location

Centre Hôspitalier de Cholet

Cholet, 49300, France

Location

Centre George François Leclerc

Dijon, 21000, France

Location

Institut Daniel Hollard Groupe Hôspitalier

Grenoble, 38028, France

Location

Centre Oscar Lambret

Lille, 59020, France

Location

CHU Limoges

Limoges, 87042, France

Location

Centre Hospitalier Bretagne Sud

Lorient, 56100, France

Location

Centre Léon Bérard

Lyon, 69008, France

Location

Institut Paoli Calmettes

Marseille, 13009, France

Location

Institut Curie Site Paris

Paris, 75005, France

Location

Hôpital Saint Louis APHP

Paris, 75010, France

Location

Centre Hospitalier Perpignan

Perpignan, 66000, France

Location

Institut Jean Godinot

Reims, 51726, France

Location

Institut Curie Hôpital René Huguenin

Saint-Cloud, 92210, France

Location

Centre Paul Strauss

Strasbourg, 67065, France

Location

Institut Claudius Regaud

Toulouse, 31059, France

Location

CHU Bretonneau - Centre Henry Kaplan

Tours, 37044, France

Location

Gustave Roussy

Villejuif, 94800, France

Location

ICO Badalona

Badalona, Spain

Location

Hospital Clinic Barcelona

Barcelona, Spain

Location

HU Vall Hebron

Barcelona, Spain

Location

HU Arnau de Vilanova

Lleida, Spain

Location

CIO Clara Campal

Madrid, Spain

Location

HU Ramon y Cajal

Madrid, Spain

Location

Hospital Clínico Universitario de Valencia

Valencia, Spain

Location

Sahlgrenska University Hospital

Gothenburg, Sweden

Location

MeSH Terms

Conditions

Breast Neoplasms

Interventions

tremelimumab; durvalumab; Biopsy

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Specimen Handling; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Investigative Techniques

Study Officials

• Fabrice Andre, Prof

  Gustave Roussy, Cancer Campus, Grand Paris

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 9, 2016
• First Posted: December 20, 2016
• Study Start: February 15, 2017
• Primary Completion: July 15, 2019
• Study Completion: August 28, 2020
• Last Updated: September 30, 2020

Record last verified: 2020-09

Locations

SE (1); FR (21); ES (7)